Intracranial volume reflects the maximally attained brain size during development, and remains stable with loss of tissue in late life. It is highly heritable, but the underlying genes remain largely undetermined. In a genome-wide association study of 32,438 adults, we discovered five novel loci for intracranial volume and confirmed two known signals. Four of the loci are also associated with adult human stature, but these remained associated with intracranial volume after adjusting for height. We found a high genetic correlation with child head circumference (ρgenetic=0.748), which indicated a similar genetic background and allowed for the identification of four additional loci through meta-analysis (Ncombined = 37,345). Variants for intracranial volume were also related to childhood and adult cognitive function, Parkinson’s disease, and enriched near genes involved in growth pathways including PI3K–AKT signaling. These findings identify biological underpinnings of intracranial volume and provide genetic support for theories on brain reserve and brain overgrowth.
Cross-sectional estimates of age-related changes in brain structure and function were compared with 6-y longitudinal estimates. The results indicated increased sensitivity of the longitudinal approach as well as qualitative differences. Critically, the cross-sectional analyses were suggestive of age-related frontal overrecruitment, whereas the longitudinal analyses revealed frontal underrecruitment with advancing age. The cross-sectional observation of overrecruitment reflected a select elderly sample. However, when followed over time, this sample showed reduced frontal recruitment. These findings dispute inferences of true age changes on the basis of age differences, hence challenging some contemporary models of neurocognitive aging, and demonstrate age-related decline in frontal brain volume as well as functional response.attrition | frontal lobe | multimodal | reorganization
The brain is not idle during rest. Functional MRI (fMRI) studies have identified several resting-state networks, including the default mode network (DMN), which contains a set of cortical regions that interact with a hippocampus (HC) subsystem. Age-related alterations in the functional architecture of the DMN and HC may influence memory functions and possibly constitute a sensitive biomarker of forthcoming memory deficits. However, the exact form of DMN-HC alterations in aging and concomitant memory deficits is largely unknown. Here, using both task and resting data from 339 participants (25-80 y old), we have demonstrated agerelated decrements in resting-state functional connectivity across most parts of the DMN, except for the HC network for which agerelated elevation of connectivity between left and right HC was found along with attenuated HC-cortical connectivity. Elevated HC connectivity at rest, which was partly accounted for by age-related decline in white matter integrity of the fornix, was associated with lower cross-sectional episodic memory performance and declining longitudinal memory performance over 20 y. Additionally, elevated HC connectivity at rest was associated with reduced HC neural recruitment and HC-cortical connectivity during active memory encoding, which suggests that strong HC connectivity restricts the degree to which the HC interacts with other brain regions during active memory processing revealed by task fMRI. Collectively, our findings suggest a model in which age-related disruption in cortico-hippocampal functional connectivity leads to a more functionally isolated HC at rest, which translates into aberrant hippocampal decoupling and deficits during mnemonic processing.hippocampus | DMN | resting state | episodic memory | aging T he brain is not idle at rest (1). Rather, intrinsic neuronal signaling, which manifests as spontaneous fluctuations in the blood oxygen level-dependent (BOLD) functional MRI (fMRI) signal, is ubiquitous in the human brain and consumes a substantial portion of the brain's energy (2). Coherent spontaneous activity has been revealed in a hierarchy of networks that span large-scale functional circuits in the brain (3-6). These resting-state networks (RSNs) show moderate-to-high test-retest reliability (7) and replicability (8), and some have been found in the monkey (9) and infant (10) brain. In the adult human brain, RSNs include sensory motor, visual, attention, and mnemonic networks, as well as the default mode network (DMN). There is evidence that the DMN entails interacting subsystems and hubs that are implicated in episodic memory (11-13). One major hub encompasses the posterior cingulate cortex and the retrosplenial cortex. Other hubs include the lateral parietal cortex and the medial prefrontal cortex. In addition, a hippocampus (HC) subsystem is distinct from, yet interrelated with, the major cortical DMN hubs (12,14).The functional architecture of the DMN and other RSNs is affected by different conditions, such as Alzheimer's disease (AD), Parkinson...
Quantitative, attrition-corrected assessment of longitudinal changes in memory can reveal substantial heterogeneity in aging trajectories, and genetic and lifestyle factors predict such heterogeneity.
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